Two series of studies examining the functional status of brain monoamine systems were completed this year. Using the serotonin agonist fenfluramine in a neuroendocrine challenge paradigm, reduced prolactin responses to fenfluramine were found in a large general sample of depressed patients compared to controls, as well as in a smaller sample of patients carefully age- and sex-matched with controls. To evaluate whether this response difference might represent a presynaptic alteration dependent upon the availability of serotonin for release or a serotonin receptor difference, we are currently using the direct serotonin receptor agonist in the same paradigm in further psychiatric patient groups and controls. We have also completed several sets of studies of the status of brain catecholamine responsivity to the selective Alpha2-adrenergic agonist clonidine. Dampened plasma MHPG and heart rate responses but greater plasma cortisol reductions following clonidine were found in depressed patients compared to controls, indicative of alterations in Alpha2-adrenergic regulation of catecholamine function in depression. While we have previously found that antidepressant drug treatment modifies these abnormal cardiovascular and MHPG responses to clonidine, no similar changes were observed in platelet Alpha2-adrenergic receptors or cyclic AMP responses to norepinephrine, suggesting that this cell may not be as useful a model for evaluating central receptor adaptive events as had been postulated previously.